Loss-of-function mutations in the NF1 tumor suppressor gene underlie the familial cancer syndrome neurofibromatosis type 1. More recently NF1 mutations have been detected in sporadic tumors, suggesting that NF1 plays an even broader role in human cancer. The overall goal of this application is to elucidate the molecular mechanisms by which NF1 inactivation promotes tumorigenesis. The NF1- encoded protein, neurofibromin, functions as a Ras-GTPase activating protein (RasGAP). Accordingly, deregulation of Ras contributes to NF1 development; however, the precise molecular function of neurofibromin remains unclear. Thus the goals of this application are to 1) establish a new function of neurofibromin and define a novel effector pathway involved in tumorigenesis and 2) systematically define the NF1 tumor suppressor network as it relates to the Ras pathway. An additional goal is to elucidate how NF1 mutations participate in a previously unrecognized sporadic tumor-type. To accomplish these aims we will be using cell biological, genetic, biochemical and some mouse modeling approaches. Collectively these studies will not only provide a comprehensive understanding of how neurofibromin regulates the Ras pathway, should identify the most critical therapeutic targets in this pathway, which may ultimately impact therapeutic development and treatments. PUBLIC HEALTH RELEVANCE: The goal of this application is to investigate how mutations in the NF1 tumor suppressor promote cancer. This research will improve our understanding of the familial cancer syndrome NF1 and will also provide insight into other sporadic cancers, such as brain cancer and melanoma. This work is also likely to impact therapeutic development for these diseases.